Chemotherapy with or without surgery

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

In the legacy (A3961 [NCT00003093]) study, the administration of neoadjuvant chemotherapy facilitated at least a partial resection of 99.6% of previously unresectable tumors. No significant difference was noted in OS according to the degree of resection accomplished (complete vs. incomplete) in either study.[9,11]

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

Less than 3% of patients in the ANBL0531 study received local radiation therapy, and only the patients with progressive hepatic enlargement or spinal cord compression received radiation therapy.[9]

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

Inferior EFS, but not OS, was observed among patients who had tumors with 11q loss of heterozygosity (n = 26) compared with those who had tumors without 11q loss of heterozygosity (n = 314) (10-year EFS rates, 68.4% vs. 83.9%; P = .03; 10-year OS rates, 88.0% vs. 95.7%; P = .09).[10]

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

The 3-year EFS rate was 92% for patients with stage 3 disease with favorable histopathology (n = 269); 90% for patients with stage 4S disease and unfavorable biology, including diploidy or unfavorable histology (n = 31); and 81% for infants with stage 4 disease (n = 176) (P < .001 for stages 3 and 4S vs. stage 4).

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

Infants with stage 4 disease with favorable biology (n = 61) had a superior 10-year EFS, compared with those with confirmed unfavorable biology tumors (n = 47) (10-year EFS rate, 86.9% vs. 66.8%; P = .02), although OS was not significantly different (10-year OS rate, 95.0% vs. 84.4%; P = .08).[10]

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

Only infants were stratified by ploidy. Those with diploid tumors received eight versus four cycles of chemotherapy. The 3-year OS rate estimates were 98% for stage 3 disease, 97% for stage 4S disease, and 93% for stage 4 disease (P = .002 for stages 3 and 4S vs. stage 4). Infants with diploidy had a poorer outcome (P = .03), as did all patients with diploidy studied, when combined (P = .03).

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

In patients with favorable biological features, there was no difference in OS between those who received eight cycles of chemotherapy (100%) for persistent disease and those who received four cycles (96%).

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

There was no unexpected toxicity.

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

Patients who had not achieved a PR (n = 27) (after completing therapy with eight cycles of carboplatin, cyclophosphamide, doxorubicin, and etoposide) were then treated with cyclophosphamide and topotecan to reach a PR. These patients had an inferior EFS than those who did not require cyclophosphamide and topotecan to reach a PR.

The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]

During long-term follow-up beyond 3 years, there were only three patients who experienced disease relapse, suggesting that ongoing surveillance beyond that time point may not be useful.[10]

A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3; histologically verified; and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by the tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery because of age or organ involvement were observed without chemotherapy.[5]

A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3; histologically verified; and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by the tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery because of age or organ involvement were observed without chemotherapy.[5]

The 3-year OS rate was excellent (95%) for infants who received chemotherapy.

A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3; histologically verified; and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by the tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery because of age or organ involvement were observed without chemotherapy.[5]

Further surgery was avoided in 33 infants, and chemotherapy was avoided in 72 infants.

A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3; histologically verified; and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by the tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery because of age or organ involvement were observed without chemotherapy.[5]

The 3-year OS rate for the infants who were observed without treatment was 99%. The metastases-free survival rate was 94% for infants with unresected tumors and did not differ from the rate for infants treated with surgery or chemotherapy (median follow-up, 58 months).

A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3; histologically verified; and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by the tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery because of age or organ involvement were observed without chemotherapy.[5]

Forty-four of 93 infants with unresected tumors experienced spontaneous regression (17 were complete regressions), and 39 infants experienced progression.

A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3; histologically verified; and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by the tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery because of age or organ involvement were observed without chemotherapy.[5]

The investigators suggested that a wait-and-see strategy is appropriate for infants with localized neuroblastoma because regressions have been observed after the first year of life.

Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (EURO-INF-NB-STUDY-1999-99.1). About one-half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects.[12][Level of evidence C1]

Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (EURO-INF-NB-STUDY-1999-99.1). About one-half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects.[12][Level of evidence C1]

The 5-year OS rate was 99%, and the EFS rate was 90% (median follow-up, 6 years).

Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (EURO-INF-NB-STUDY-1999-99.1). About one-half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects.[12][Level of evidence C1]

In this study, infants who underwent surgical resection had a better EFS than did those who did not have surgery.

In two European prospective trials of infants with disseminated neuroblastoma without MYCN gene amplification, infants with INSS stage 3 primary or positive skeletal scintigraphy without radiological bone metastasis (identified mostly by MIBG scan, but a few with just technetium Tc 99m bone scan) were not administered chemotherapy unless life-threatening or organ-threatening symptoms developed. When given, chemotherapy consisted of short and standard doses.[13]

In two European prospective trials of infants with disseminated neuroblastoma without MYCN gene amplification, infants with INSS stage 3 primary or positive skeletal scintigraphy without radiological bone metastasis (identified mostly by MIBG scan, but a few with just technetium Tc 99m bone scan) were not administered chemotherapy unless life-threatening or organ-threatening symptoms developed. When given, chemotherapy consisted of short and standard doses.[13]

The OS rate was 100% in the 41 patients who did not have INSS stage 4S, regardless of initial chemotherapy.

In two European prospective trials of infants with disseminated neuroblastoma without MYCN gene amplification, infants with INSS stage 3 primary or positive skeletal scintigraphy without radiological bone metastasis (identified mostly by MIBG scan, but a few with just technetium Tc 99m bone scan) were not administered chemotherapy unless life-threatening or organ-threatening symptoms developed. When given, chemotherapy consisted of short and standard doses.[13]

In infants with overt metastases to the skeleton, lung, and central nervous system (by radionuclide scan, but not by plain x-ray or computed tomography [CT] scan), the 2-year OS rate was 96% (n = 45).

In two European prospective trials of infants with disseminated neuroblastoma without MYCN gene amplification, infants with INSS stage 3 primary or positive skeletal scintigraphy without radiological bone metastasis (identified mostly by MIBG scan, but a few with just technetium Tc 99m bone scan) were not administered chemotherapy unless life-threatening or organ-threatening symptoms developed. When given, chemotherapy consisted of short and standard doses.[13]

No patients died of surgery-related or chemotherapy-related complications on either protocol.

A retrospective analysis from the COG evaluated patients aged 12 to 18 months with metastatic disease and favorable biological features. In legacy trials, these patients were treated with high-risk disease regimens.[14]

A retrospective analysis from the COG evaluated patients aged 12 to 18 months with metastatic disease and favorable biological features. In legacy trials, these patients were treated with high-risk disease regimens.[14]

This analysis demonstrated that this group of patients had similar excellent outcomes with intermediate-risk therapy, compared with high-risk therapy. These patients are now treated with intermediate-risk therapy in current clinical trials.

A prospective International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) trial treated infants with MYCN-nonamplified, stage 2 or stage 3 unresectable neuroblastoma, as well as those aged 12 to 18 months who had favorable INPC.[15][Level of evidence C2]

A prospective International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) trial treated infants with MYCN-nonamplified, stage 2 or stage 3 unresectable neuroblastoma, as well as those aged 12 to 18 months who had favorable INPC.[15][Level of evidence C2]

The EFS rate was 98% with conventional chemotherapy.

A prospective International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) trial treated infants with MYCN-nonamplified, stage 2 or stage 3 unresectable neuroblastoma, as well as those aged 12 to 18 months who had favorable INPC.[15][Level of evidence C2]

These results are similar to results from the COG-A3961 trial.